Quinones are a unique class of organic compound identified by the presence of a cyclic diketone structure. The simplest example is 1,4-benzequinone (BQ). BQ consists of a single benzene ring flanked by 2 ketone [R—C(═O)] groups at the 1st and 4th carbons. 9-10-anthraquinone (AQ) is only slightly more complex. AQ is derived from the 3 ring aromatic structure anthracene. Anthraquinones constitute a large and diverse subgroup within the quinone superfamily. Anthraquinone based drugs are clinically used as laxatives and chemotherapeutic agents. In addition, they show promise as treatments for malaria, and multiple sclerosis.
Natural anthraquinones have a brilliant range of colors and were used as dyeing agents since antiquity. Recent studies show that some natural anthraquinones exhibit unique medicinal properties. Preliminary evidence suggests that the natural anthraquinone emodin (6-methyl-1,3,8-trihydroxyanthraquinone) is an especially promising neuroprotective drug with possible indications for the treatment of chronic neurodegenerative disease. Emodin prevents neuronal death in cell culture models of degenerative pathology. Alzheimer's disease is characterized by excessive accumulation of two key pathological proteins in the brain, beta-amyloid (Aβ plaques) and the microtubule associated tau (tau tangles). The dysfunctional regulation and hyperphosphorylation of tau leads to protein misfolding. In turn, tau proteins dimerize to form cytotoxic tangles in afflicted neurons. (i.e. tauopathy). Pickhardt et al. used genetically modified neuroblastoma cells, engineered to overpress aberrant tau, and screened for tauopathy inhibitors. Emodin efficiently inhibited tau aggregation in this system.
The anti-aggregation activity of emodin may be a trait shared amongst many anthraquinone derivatives. Colombo et al. found that the chemotherapeutic anthraquinones mitoxantrone and pixantrone prevent aggregation of toxic (soluble) Aβ-1-42. Furthermore, pixantrone inhibited Aβ-1-42 tocixity in neuroblastoma cells. Similarly, Convertino et al. investigated the structural intercalation of AQ with β-amyloid sheets, and found that it efficiently inhibited aggregation of the Aβ-1-40 fragment.
Incubation of pathological Aβ induces cell death of primary neurons. Liu et al. reported that 24 hour emodin pretreatment protected cultured cortical neurons from subsequent injury induced by incubation with the highly toxic Aβ-25-35 fragment. The beneficial effect of emodin was blocked by addition of the phosphatidylinositol-3-kinase (PI3K)/AKT inhibitor LY294002. The result indicates that PI3K/AKT is an important survival mechanism activated by emodin in this study. However, it is unclear if emodin directly activates AKT signaling. Arguing against a direct role for AKT activation in this model, Aβ-25-35 is reported to robustly inhibit endogenous AKT activity in both primary neurons and cerebrovascular endothelial cells. Therefore, emodin (as an aggregate inhibitor) may simply relieve Aβ-25-35 induced AKT repression. Moreover, studies in cancer cells report that emodin is a potent PI3K inhibitor (IC50 3.3 μM); certainly a contradiction to an AKT activator.
The challenges of treating acute brain injury are uniquely different from managing a chronic neurodegenerative disease. The mechanisms of neuronal death are highly variable (depending on type of brain injury), and the time window for therapeutic intervention is often short. Limited evidence supports a protective role for emodin (and related natural anthraquinone compounds) in ischemic brain injury. Oxidative damage is an important component of acute ischemic injury. Pretreament of cultured cortical neurons with emodin prevents subsequent injury by 150 μM H2O2. Similarly, cotreatment with 50 μM danthron (1,8-dihydroxyanthraquinone) protects mixed neuron-glial cultures in five models of oxidative injury. Neuroprotection was observed in the presence of Aβ-25-35, Fe3+ peroxidation, buthionine sulfoximine (BSO) induced glutathione depletion, nitric oxide radical production, or H2O2. Interestingly, in this same study, the authors report danthron was ineffective against zinc toxicity, xanthine/xanthine oxidase O2 radicals, NMDA, kainate, STS, or dextromethorphan. These results show that danthron is preferentially neuroprotective in models of progressive oxidative stress.
Finally, a recent study found that the emodin analogue, emodin-8-O-beta-D-glucoside, was able to pass through the blood brain barrier (BBB) and reduce infarct volume after focal cerebral ischemia. The authors report a significant rise in the activity of endogenous antioxidant superoxide dismutase (SOD) following experimental drug treatment. Consistent with increased SOD, malondialdehyde (MDA), a measure of lipid peroxidation, was decreased in emodin-glucoside treated animals. Altogether the evidence suggests that natural anthraquinones boost antioxidant defenses, which may contribute to their neuroprotective actions in models of acute brain injury.
Pretreatment with natural anthraquinones promote antioxidant survival mechanisms and reduce oxidative stress. However, the time course to induce this protective response is unknown. In clinical practice, most opportunities to treat acute brain injury are restricted to the post-injury period. Emodin has not been tested using an in vitro post-treatment study design. For anthraquinones to be viable drug candidates in the field of acute brain injury, evidence should support their efficacy when administered after injury.